Hypertrophic Cardiomyopathy: Aetiology & Characteristics

• Hypertrophic cardiomyopathy involves an asymmetrical increase in left ventricular wall thickness, not solely explained by abnormal loading conditions
• It is typically inherited via an autosomal dominant pattern with mutations in cardiac sarcomere protein genes
• The estimated prevalence is 1 in 500, commonly presenting in young adults

Aetiology

• Hypertrophic cardiomyopathy is primarily a genetic condition affecting sarcomeric proteins like beta-myosin heavy chain, myosin-binding protein C, and cardiac troponin C
• The penetrance and expression of responsible genes vary, leading to complex presentations
• Diversity in causal mutations and their expression results in a range of phenotypes, each with different genetic and molecular mechanisms

Disease characteristics

• Asymmetrical left ventricular wall thickening, typically of the septum, is a primary feature
• Thickening can occur in any part of the ventricle
• Other pathological features include myocardial fibrosis/disarray, systolic anterior motion of the mitral valve, and abnormal coronary microcirculatory function
• It commonly presents in the third decade of life
• It is more common in men, however presents younger in women, and women tend to be more symptomatic than men

Risk factors

• A family history is the only risk factor, given it is mostly inherited

Clinical features

History

• Typical symptoms include:
• Dyspnoea (90%): Due to left ventricular diastolic dysfunction and resultant pulmonary oedema
• Syncope and presyncope: Due to inadequate cardiac output (especially on exertion) or arrhythmias, and indicate a high risk for sudden cardiac death
• Chest pain: Due to microvascular complications or mismatch between increased oxygen requirement of the hypertrophied myocardium and reduced perfusion due to impaired diastolic relaxation
• Palpitations: Due to arrhythmias, both supraventricular and ventricular in origin
• Family history: Includes sudden cardiac death, unexplained heart failure, cardiac transplantation or implantable cardioverter-defibrillator (ICD) insertion, and can identify other at-risk family members

Clinical examination

• Cardiovascular examination is required for suspected patients
• Findings are often unremarkable and unspecific
• Clinical findings can include:
• Systolic ejection murmur loudest between the apex and left sternal border: Indicative of left ventricular outflow tract obstruction (accentuated with Valsalva manoeuvre)
• Fourth heart sound (S4) of atrial systole against a non-compliant ventricle
• Holosystolic murmur loudest at the apex or axilla: Indicative of mitral regurgitation
• Double apical beat of ventricular contraction and left atrial contraction against hypertrophic ventricle
• Lateral displacement of the apical pulse
• Splitting of the second heart sound
• Prominent a wave: Indicative of the reduced right ventricular compliance with massive left ventricular hypertrophy

Differential diagnoses

• It's important to differentiate from other causes of left ventricular hypertrophy including hypertension, aortic stenosis, athletic heart, and cardiac amyloidosis
• Detailed history is essential for making this distinction, as well as a thorough review of past medical and family history
• Other less common differential diagnoses include:
• Metabolic disorders (e.g. Anderson-Fabry disease, Pompe disease)
• Primary mitochondrial disease
• Neuromuscular disease (e.g. Friedreich’s ataxia)
• Malformation syndromes (e.g. Noonan syndrome, LEOPARD syndrome)

Investigations

Bedside investigations

• Blood pressure: exclude hypertension
• Electrocardiography (ECG): Left ventricular hypertrophy manifests as increased voltages in precordial leads and non-specific ST-segment and T-wave abnormalities. Deep, narrow Q-waves are common. P-mitrale reflects left atrial dilatation.
• Ambulatory electrocardiography (ECG): Forms part of initial risk assessment. Primary findings of interest include asymptomatic non-sustained ventricular tachycardia (NSVT) and paroxysmal supraventricular arrhythmias (SVT).

Laboratory investigations

• Full blood count: Look for anaemia
• Urea and electrolytes: For renal dysfunction
• Liver function tests: For liver dysfunction
• Thyroid function tests: Thyroid disease can exacerbate left ventricular dysfunction
• NT-proBNP: Quantify the degree, if any, of heart failure

Imaging

• Echocardiography is the first-line investigation in diagnosing and managing patients
• Asymmetrical left ventricular wall thickness ≥15mm in one or more left ventricular myocardial segments in diastole, with no other abnormal loading conditions, is suggestive of the diagnosis
• Modalities include:
• Transthoracic echocardiography (TTE): Assess left ventricular wall thickness during diastole; left ventricular outflow tract obstruction (using Doppler mode); valve abnormalities include systolic anterior motion of the mitral valve; left atrial enlargement and diastolic dysfunction
• Exercise stress echocardiography: Indicated in symptomatic patients with no left ventricular outflow tract obstruction identified with Valsalva manoeuvre
• Transoesophageal echocardiography (TOE): Indicated if images of left ventricular outflow tract mechanism or valve abnormalities are poorly visualised
• Other relevant imaging investigations include:
• Cardiac magnetic resonance imaging (cMRI): Consider as part of a thorough assessment if local resources and expertise permit, however, it is not required for diagnosis
• Cardiac computed tomography (cCT): Consider in patients with poor echocardiography images and contraindications to magnetic resonance imaging

Specialist tests

• Cardiopulmonary exercise testing: Recommended in all patients and provides functional information about the patient’s cardiac function
• Electrophysiological testing: Indicated if proven persistent or recurrent supraventricular tachycardia or in patients with ventricular pre-excitation

Management

• General lifestyle advice includes avoiding dehydration and alcohol, encouraging weight loss and safety netting for symptoms of deterioration

Angina

• Beta-blockers and calcium channel blockers can be used in patients with prolonged or exertional angina-like chest pain in the absence of significant left ventricular outflow tract obstruction and coronary artery disease
• Safe use of oral nitrates relies on the exclusion of left ventricular outflow tract obstruction and, if used, should be done so cautiously

Atrial fibrillation

• The prevalence of it in patients is 22.5%
• Two greatest predictors for paroxysmal or permanent atrial fibrillation are age and left atrial enlargement
• If left atrial diameter is ≥45mm, the patient should undergo 6 to 12 monthly, 48-hour ambulatory electrocardiogram monitoring to exclude atrial fibrillation
• Management depends on the haemodynamic status of the patient:
• Haemodynamically unstable: emergency direct current cardioversion
• Haemodynamically stable: beta-blockers or verapamil/diltiazem
• Digoxin is not suitable in patients with left ventricular outflow tract obstruction and a normal ejection fraction
• Flecainide should be avoided as it may prolong the QT interval
• Anticoagulation is recommended in all patients with atrial fibrillation given their younger age and elevated risk of thromboembolic events
• CHA2DS2-VASc scoring is not appropriate
• HAS-BLED scoring can be used to evaluate a patient’s risk of bleeding
• Warfarin is the anticoagulant of choice
• Novel oral anticoagulants are only indicated if warfarin is not tolerated

Heart failure

• It is divided depending on the patients’ ejection fraction
• In severe cases, cardiac resynchronisation therapy and cardiac transplant may be considered
• Preserved ejection fraction: reduce left ventricular diastolic pressure and improve left ventricular filling with beta-blockers, verapamil or diltiazem and, if indicated, loop diuretics
• Reduced ejection fraction: a threshold ejection fraction of 50mmHg then septal reduction therapy is indicated